SYSTEMATIC QUANTITATIVE ANALYSIS OF NF-kappaB CO-ACTIVATORS

炎症是对感染和损伤的正常生理反应，但当过度引发时可导致广泛的组织损伤和残疾。持续炎症反应的病理后果包括各种自身免疫性疾病，如类风湿性关节炎、克罗恩病、强直性脊柱炎和多发性硬化。持续的炎症反应通常与炎症分子产生调节的破坏有关。在对感染或损伤的正常的自我解决身体反应中，炎症分子在限定的时间段内产生，而在慢性自身免疫性疾病中，它们的产生延长。许多炎症分子的产生是由称为NF-κ B的关键调节蛋白家族控制的。调节这些转录因子水平和恢复正常细胞因子平衡的方法被认为具有潜在的治疗重要性。但NF-κ B并不是孤立发挥作用的。许多NF-κ B依赖性免疫基因也受到其他普遍存在的转录因子的共调节，包括由九种蛋白质组成的转录因子的IRF（干扰素调节因子）家族。哪些IRF蛋白能够与NF-κ B协同调节基因表达，以及这种协同调节如何依赖于吸引这些因子的基因组元件的序列是本研究的主题。了解成功炎症反应的基本要素对于设计抑制炎症的靶向策略同时保留宿主防御所需的信号非常重要。这也将帮助科学家们更好地理解为什么人类有这么多表面上相似的蛋白质家族，以及它们具有什么特定的功能。这项研究将由两个小组进行：帝国理工学院肯尼迪流变学研究所的伊琳娜·乌达洛娃博士和牛津大学威康信托人类遗传学中心的扬尼斯·拉古西斯博士。它将以实验室为基础，并将使用新的基因组技术和计算方法。这项新技术将取代动物研究。本研究产生的结果将通过同行评审的科学期刊和各研究所的年度报告进行传播，并在科学会议上提出。

Inflammation is a normal physiological response to infection and injury, but can lead to extensive tissue damage and disability when elicited in excess. Pathological consequences of sustained inflammatory response include variety of autoimmune diseases, such as rheumatoid arthritis, Crohn s disease, ankylosing spondylitis and multiple sclerosis. A sustained inflammatory response is often linked to the break down in regulation of production of inflammatory molecules. In a normal self-resolving body response to infection or injury inflammatory molecules are produced for a defined period of time, while in chronic autoimmune conditions their production is prolonged. The production of many inflammatory molecules is controlled by a key family of regulatory proteins called NF-kappaB. Ways to modulate levels of these transcription factors and restore a normal cytokine balance are considered to be of a potential therapeutic importance. But NF-kappaB does not function in isolation. Many of the NF-kappaB dependent immune genes are also co-regulated by other ubiquitous transcription factors, including the IRF (interferon regulatory factor) family of transcription factors consisting of nine proteins. Which IRF proteins are able to synergise with NF-kappaB to regulate gene expression, and how this co-regulation is dependent on the sequence of genomic elements attracting these factors is the subject of this investigation. Understanding the basic elements underlying successful inflammatory response is important for designing targeted strategies for suppressing inflammation while preserving signals required for host defence. It will also help scientists to better understand why humans have so many families of ostensibly similar proteins and what specific functions they hold.The research will be carried out by two groups: of Dr Irina Udalova at the Kennedy Institute of Rheumatology, Imperial College, and of Dr Ioannis Ragoussis at the Wellcome Trust Centre for Human Genetics, Oxford University. It will be laboratory based and will use novel genomic techniques and computational methods. The proposed novel techniques will replace the use of animals in research. Results generated in this study will be communicated through peer-reviewed scientific journals and through annual reports from respective Institutes and presented at scientific meetings.